Dehydroepiandrosterone (DHEA), also known as 3-beta-hydroxyandrost-5-en-17-one, dehydroisoandrosterone, trans-dehydroandrosterone, Δ5-androsten-3-β-ol-17-one, and prasterone is a naturally occurring intermediate formed in the course of synthesis of various steroids from cholesterol. DHEA is the most abundant steroid hormone in humans and is produced mainly by the adrenal cortex as an inactive sulfate ester (DHEA-S). DHEA production also occurs in the testes, ovaries, and brain.
DHEA has been implicated in a broad range of biological effects in humans and other mammals. It acts on the androgen receptor both directly and through its metabolites, which include androstanediol and androstenedione, which can undergo further conversion to produce the androgen testosterone and the estrogens estrone, estradiol, and estriol.
DHEA has been proposed for use in treating many medical conditions, such as systemic lupus erythematosus, primary adrenal insufficiency, Addison's disease, reduced libido, obesity, osteoporosis, fibromyalgia and benign gynaecological conditions such as endometriosis. It has also been suggested to employ DHEA in female hormonal oral contraceptives with the aim to prevent testosterone loss and maintaining physiological androgen levels (WO 2003/041719). The issue of loss of androgens, especially testosterone, is a potential problem experienced by all women using hormonal oral contraceptives.
DHEA can be administered by different routes. Unlike various other known androgens, DHEA is orally active. Applicant has found that daily administration of DHEA in an oral dosage of around 50 mg to female users of hormonal oral contraceptives normalizes total testosterone completely and free testosterone for at least 50%, without causing excessively high testosterone levels or clinical symptoms of hyperandrogenicity and without increasing estradiol levels. Apart from the ability of DHEA to restore and normalize androgen levels, important significant clinical benefits have been observed on several aspects of sexual function (arousability, responsivity, genital sensation, lubrication), mood and menstrual distress symptoms.
Thus, it would be desirable to include DHEA in, for instance, oral contraceptive tablets. However, oral contraceptive tablets are relatively small, typically having a mass of about 80 mg. Incorporation of about 50 mg DHEA in a tablet of about 80 mg poses a real challenge as in such a tablet DHEA inevitably becomes the main component, leaving very little room for other constituents that are normally used in tablets to enable tabletting, to promote dissolution, to prevent retrogradation etc.
Oral dosage units containing DHEA are known in the art. US 2005/137178 describes a method of treating or reducing the risk of acquiring hypercholesterolemia comprising administering a therapeutically effective amount of a dehydroepiandrosterone. Oral dosage units containing up to 15 wt. % DHEA are described in the examples of this U.S. patent application.
Corvi Mora et al. (Development of a sustained-release matrix tablet formulation of DHEA as ternary complex with α-cyclodextrin and glycine, J Incl Phenom Macrocycl Chem (2007) 57, 699-704) describes a sustained release tablet having a weight of 550 mg and containing 25 mg DHEA.
WO 2004/105694 relates to pharmaceutical compositions comprising an active agent; a vitamin E substance; and a surfactant. In the examples a pharmaceutical composition is described that has a total weight of 675 mg and that contains 100 mg DHEA.
WO 2010/145010 is concerned with the reduction or elimination of the incidence of hot flushes, vasomotor symptoms and night sweats by administering a combination of a (i) sex steroid precursor, such as DHEA, and (ii) a selective estrogen receptor modulator or an antiestrogen. The examples of the international application describe a gelatin capsule containing 25 wt. % DHEA.